International Journal of Pharmaceutics最新文献

Irinotecan is widely used in cancer therapy but is limited by significant toxicities due to systemic and intestinal exposure to its active metabolite, SN-38. To improve its therapeutic profile, irinotecan has been encapsulated in pegylated liposome as a nano-liposomal form (nal-IRI) to modify its pharmacokinetics (PK) and enhance tumor delivery via the enhanced permeability and retention effect. While nal-IRI has shown clinical benefits, the formulation-specific PK and pharmacodynamics (PD) underlying its efficacy and safety remain unknown. This study aimed to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model to compare the disposition and tumor response of irinotecan and SN-38 following administration of free irinotecan (free-IRI, Camptosar®) and nal-IRI (Onivyde®) in pediatric tumor xenografts. Plasma and tissue PK data (liver, spleen, kidney, brain, lung, and tumor) were collected from healthy and tumor-bearing mice treated with various intravenous doses of both formulations. The model accurately described plasma, tissue, and tumor concentrations of irinotecan and SN-38. Key determinants of disposition included enterohepatic recycling, carboxylesterase-mediated conversion in liver/plasma, and clearance through biliary/metabolic pathways for irinotecan, and biliary/renal routes for SN-38. Nal-IRI exhibited formulation-specific characteristics, including phagocyte-mediated uptake, non-linear plasma clearance, liposomal release and permeability-limited tissue distribution, that are major determinants of nal-IRI disposition. PD modeling indicated intra-tumoral SN-38 exposure was the principal driver of antitumor efficacy. Nal-IRI achieved sustained and higher SN-38 tumor exposure, producing more rapid and durable tumor suppression than free-IRI. This integrated PBPK/PD framework provides mechanistic insights into the enhanced efficacy of nal-IRI and supports its optimized use in irinotecan-based cancer therapy.

The toxicological evaluation of excipients plays a crucial role in the development of SEDDS. This study examined key formulation components to identify critical factors influencing cellular tolerance and supports the design of biocompatible SEDDS. Physicochemical properties of various oils, co-solvents, co-surfactants, non-ionic and charged surfactants formulated in SEDDS were determined via dynamic light scattering, while oxidative stability of selected surfactants was assessed through hydroperoxide quantification. Biological compatibility was evaluated by analyzing hemolytic effects on human erythrocytes and cell viability in CaCo-2 and HEK-293 cells. Metabolic activity and proliferation were additionally measured photometrically via MTT test. Cellular compatibility varied markedly among individual excipients, depending on their chemical structure and formulation role. In lipid-based systems, saturated triglycerides yielded up to sixfold higher viability than free fatty acids. Co-solvent toxicity correlated with lipophilicity and functional groups: isopropanol induced early membrane stress in CaCo-2 cells, while glycerol caused delayed hemolysis after 48  h. A clear structure-activity relationship emerged across surfactant types. PEG-based surfactants outperformed fatty alcohols and sugar-based formulations, which reached IC₅₀ values below 0.01% after 24  h and triggered early proliferation loss. This trend aligned with peroxide levels, as surfactants < 10  mM consistently maintained high CaCo-2 viability and stable IC₅₀ values, exemplified by polyoxyl 40 hydrogenated castor oil. Among zwitterionic surfactants, phosphatidylcholine showed highest biocompatibility, causing only a twofold reduction in hemolytic activity after 48  h, whereas cocoamidohydroxypropyl sulfobetaine induced an 12-fold decrease within 3  h. These findings underscore the role of excipient selection in minimizing cellular stress and adverse drug reactions in oral lipid-based drug delivery.